nutritional insights - mycmeglobally in recent years, and more than half of infants with atopic...
TRANSCRIPT
The prevalence of food allergy has increased globally in recent
years, and more than half of infants with atopic der-matitis (AD)—generally the first manifestation of atopy—develop other aller-gic disease by the time they are 3 years old. Given this situation, primary allergy prevention (avoiding onset of immunoglobulin E [IgE] sensitization) has become increasingly important, noted David M. Fleischer, MD, associate professor of pediatrics, University of Colorado Denver School of Medicine. The timing of introduction of comple-mentary allergenic foods and the role of hydrolyzed formulas in high-risk infants who are not exclusively breastfed are par-ticularly relevant to this goal.
A new look at delayed introduction of highly allergenic foods. In past years, the American Academy of Pediatrics (AAP) and other professional groups recommend-ed delaying the introduction of highly allergenic foods, such as egg, peanut, tree nuts, and fish, for 1 to 3 years depending on the food. Since 2000, however, think-ing has shifted because of observational studies showing that early introduction of allergenic foods may actually prevent food allergy. And in 2015, a randomized con-trolled trial found that early introduction of peanut significantly decreased the fre-
quency of development of peanut allergy among high-risk children.1
Investigators divided 640, 4- to 11-month-old infants with severe AD, egg allergy, or both into 2 groups: those with a positive skin-prick test for peanut allergy in 1 group and those without a positive test in the other. Infants in each of these groups then were divided
into another 2 groups: those assigned to eating peanuts (in the form of Bamba, a peanut butter snack) or to not eating pea-nuts until they were 60 months (5 years) old. At the end of the 5-year study period, of the infants who did not have a positive skin-prick test for peanut allergy, 13.7% in the avoidance group had peanut allergy compared with 1.9% in the Bamba-consuming group. Of the infants with a positive skin-prick test, only 10.6% of those consuming peanuts had developed peanut allergy vs 35.3% of those who had consumed no peanut.
Other studies also have suggested that early introduction of a variety of highly allergenic foods may reduce the risk of food allergy, while delayed introduction may increase this risk or of asthma or AD. Based on numerous study results, the AAP and the American Academy of Allergy, Asthma & Immunology (AAAAI) have determined
HIGHLIGHTS from Advances in Neonatal and Pediatric Nutrition 2015 Held in San Francisco, California August 3-5, 2015
Preventing allergy: What infants eat makes a difference
C O N T E N T S
Nutritional Insights
Preventing allergy: What infants eat makes a difference
Choosing feeds to help premature infants grow as they should
Finding better strategies for optimal weight gain in premature neonates
Diet and autism: Is there a connection?
Gluten-free diets: Separating the wheat from the chaff
How good is donor milk for preterm babies?
Avoidance—The best (only!) way to manage food allergy
How “good bugs” promote good health
When the neonate is preterm/tiny, mother’s milk needs fortification
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FACULTY REVIEWERJae H. Kim, MD, PhD Associate Clinical Professor of Clinical PediatricsDirector, Neonatal-Perinatal Medicine Fellowship ProgramNutrition Director, SPIN ProgramDivisions of Neonatology and Pediatric Gastroenterology, Hepatology and NutritionUC San Diego Medical Center/Rady Children’s Hospital of San DiegoSan Diego, CA
Provided by Supported by an educational grant from
Nestlé Nutrition Institute
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Nutritional Insights
PROGRAM DESCRIPTION The goal of this enduring continuing medical education (CME) activity is to provide clinicians with a concise overview and important take-home messages of selected presentations from the Advances in Neonatal and Pediatric Nutrition 2015 Conference. The live conference, accredited and hosted by the University of California San Diego, School of Medicine, brought together pediatric clinicians to learn about various topics relating to pediatric nutrition. This enduring e-conference report aims to improve clinicians’ knowledge, competence, and performance related to: primary prevention of allergic diseases through nutritional interventions; managing food allergies in infancy and childhood; diet and autism; weight gain for the premature neonate; fortification of the preterm infant; updates on infant formulas; and shifts in the intestinal microbiota: therapeutic opportunities for prebiotics and probiotics.
LEARNING OBJECTIVESUpon completion of this educational activity, participants will be better able to:• Describe current evidence about the prevention and management of
pediatric allergic diseases• Employ strategies for weight gain in the premature neonate• Evaluate the latest developments in infant formulas• Assess the use of prebiotic and probiotic supplementation in infants• Propose practical nutritional interventions to families to improve infant
nutrition
INTENDED AUDIENCEPediatricians, pediatric nurse practitioners, pediatric physician assistants, primary care physicians, NPs, PAs, dieticians, and other healthcare professionals involved in the care of children
ACCREDITATION STATEMENTHaymarket Medical Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.The enduring material has been approved by the ACCME, whose approval is recognized by the Commission on Dietetic Registration.
CREDIT DESIGNATIONHaymarket Medical Education will designate this enduring material for a maximum of 1.50 AMA PRA Category 1 Credits™.Registered dieticians (RDs)/dietetic technicians, registered (DTRs) will be able to receive 1.50 CPEUs for participating in this enduring activity.
CONFLICT OF INTEREST DISCLOSURE POLICYIn accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards for Commercial Support, Haymarket Medical Education (HME) requires that individuals in a position to con-trol the content of an educational activity disclose all relevant financial relationships with any commercial interest. HME resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational programs. All relevant financial relationships shall be disclosed to participants prior to the start of the activity.Furthermore, HME seeks to verify that all scientific research referred to, reported, or used in a continuing medical education (CME) activity con-forms to the generally accepted standards of experimental design, data collection, and analysis. HME is committed to providing its learners with high-quality CME activities that promote improvements in healthcare and not those of a commercial interest.
REVIEWERJae H. Kim, MD, PhD Associate Clinical Professor of Clinical PediatricsDirector, Neonatal-Perinatal Medicine Fellowship ProgramNutrition Director, SPIN ProgramDivisions of Neonatology and Pediatric Gastroenterology, Hepatology and NutritionUC San Diego Medical Center/Rady Children’s Hospital of San DiegoSan Diego, CA
Dr. Kim discloses that he is in receipt of intellectual property rights/patent holder for a newborn heart rate monitor; is a consultant for Medela; is on the speakers’ bureaus for Abbott Nutrition, Mead Johnson, Medela, Nestlé Nutrition, and Nutricia; has received research funds from Ferring Pharmaceuticals and InfaCare Pharmaceutical; and is a shareholder in PediaSolutions.
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DISCLOSURE OF UNLABELED USEThis educational activity may contain discussion of approved and/or investigational uses of agents that are not indicated by the FDA. Nestlé Nutrition Institute and HME do not recommend the use of any agent out-side of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Nestlé Nutrition Institute and HME. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
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that no convincing evidence exists for delaying introduction of specific highly allergenic foods. Parents should offer them at 4 to 6 months of age, just as they do other complementary foods, except in children with severe food allergy or stubborn, moderate to severe AD—who would benefit from evalua-tion by an allergist.
When hydrolyzed formula makes sense. Because of a demonstrated asso-ciation between early exclusive breast-feeding and protection against atopic symptoms, along with other evidence, the AAAAI recommends exclusive breastfeeding for 4 to 6 months to pre-vent allergic disease. When exclusive breastfeeding is insufficient or not pos-sible, the AAAAI recommends that infants at high risk for developing aller-gy be given a hydrolyzed formula, which appears to delay or prevent AD compared with intact cow’s milk for-mula (CMF). This recommendation is based on results of the landmark German Infant Nutrition Intervention (GINI) study as well as subsequent research. GINI randomly assigned 945 high-risk infants to formula supplemen-tation with CMF, partially hydrolyzed whey formula (pHF-W), extensively hydrolyzed whey formula (eHF-W), or extensively hydrolyzed casein formula (eHF-C) for 4 months. In the first 4
months, pHF-W and eHF-C were asso-ciated with preventing AD, an effect that was still evident in a follow-up study 10 years later (see Figure 1).2
No effect was seen on asthma and allergic rhinitis or allergic sensitiza-
tion, however. Though some evidence suggests that an eHF may be a bit more beneficial than a pHF in pre-venting allergy, the evidence is not strong enough to offset the far greater costs of eHFs.
How to optimize available pre-term infant formulas and prod-ucts intended to supplement or
augment breast milk was the focus of Jacqueline Keller, MS, RD—the neo-natal intensive care unit (NICU) prin-cipal dietitian at the University of San Diego Medical Center. Noting that
“we know that human milk is the recommended basis of nutrition for the premature infant, but we cannot achieve our growth goals with human milk alone,” she presented a strategy for increasing the nutrient delivery of breast milk in the hospitalized prema-ture infant that was based on a 2014
publication of current evidence and expert opinion, and is expressed as amounts per kilogram of body weight per day and per 100 kcal of energy intake (see Table 1).3
The goal of this strategy is to achieve and maintain the rate of intrauterine growth and body composition of a healthy fetus of the same gestational age in utero.
When breast milk is not available, clinicians have a variety of nutrient-dense ready-to-feed premature formu-las from which to choose. They need to keep in mind that professional bod-
FIGURE 1. Hydrolyzed Formulas and AD Prevention: 10-year GINI Study Results
AD = atopic dermatitis; GINI = German Infant Nutrition Intervention Study; CMF = cow’s milk formula; eHF-W = extensively hydrolyzed formula–whey; pHF-W = partially hydrolyzed formula–whey; eHF-C = extensively hydrolyzed formula–casein.
Von Berg A, et al. J Allergy Clin Immunol. 2013;131:1565-1573.
Adjusted cumulative incidence of parent-reported, physician-diagnosed AD.
Age (years)
Phys
icia
n-D
iag
no
sed
AD
(ad
j. %
)
Von Berg A, et al. J Allergy Clin Immunol. 2013;131:1565-‐1573.
German Infant Nutri.on Interven.on Study: 10-‐Year Results
• 945 high risk infants randomized to formula supplementaEon with CMF vs 3 hydrolysate formulas: pHF-‐W, eHF-‐W, eHF-‐C for 4 months
• 10yr f/u with ISAAC quesEonnaire and examinaEon
• pHF-‐W and eHF-‐C formulas in the first 4 months associated with prevenEve effect on cumulaEve incidence of AD in high-‐risk children lasEng unEl 10 years
• No effect on asthma and allergic rhiniEs, or allergic sensiEzaEon
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40
35
30
25
20
15
10 9 8 7
6
0 0 1 2 3 4 5 6 7 8 9 10
Age (years)
Physician-‐diagno
sed Eczema [adj. %
]
CMF eHF-‐W pHF-‐W eHF-‐C
Adjusted cumulaEve incidence of parent-‐reported physician-‐diagnosed eczema in per-‐protocol (PP) populaEon.
Choosing feeds to help premature infants grow as they should
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NUTRITIONAL INSIGHTS
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ies, including the US Food and Drug Administration (FDA) and the AAP, recommend avoiding the use of pow-ders in the NICU because they are not commercially sterile. However, unlike in past years, many liquid products now are available, and most hospital formularies have such products. The clinicians’ challenge is to work with “the cards that are available,” Ms. Keller said.
In planning nutrition for the prema-ture infant after discharge, practitio-ners must consider birth history,
medical course and any surgery, adjusted age and growth pattern near discharge, the mother’s breast milk supply, any history of formula intoler-ance or family preference, and practi-cal matters such as family resources and insurance coverage. One basic strategy if the mother’s breast milk supply is anticipated to meet more than 75% of the infant’s daily feeding volume goal is to provide 1 oz of 30 kcal/oz premature formula 3 to 4 times a day after providing breast milk (see Figure 2).
For babies whose mothers can be expected to meet about 50% of the infant’s daily feeding volume goal, the supplemental premature post-dis-charge formula should be prepared to 24 kcal/oz, with needed adjustments to caloric density based on the babies’ rates of weight gain and how they are growing. When the anticipated breast milk supply is expected to meet less than 30% of the needed daily volume, 22 kcal/oz of premature post-dis-charge formula should be provided.
Ms. Keller also urged listeners to become more aware of some of the regulatory guidelines that influence the composition of the products that are available and their manufacture. The Infant Formula Act of 1980 gave the FDA authority over quality control for infant formula, and in 1985, acting on AAP recommendations, it issued minimum required concentrations of 29 nutrients. In 2014, the FDA updated regulations to set standards for manufacturers of nonexempt infant formula (products intended for healthy, term infants), including testing for Salmonella and Cronobacter sakazakii as well as testing the final product for nutrient content before it enters the market and at the end of the product’s shelf life. Ms. Keller noted that nonexempt formula is subject to more detailed standards than exempt infant formulas (those used in the NICU).
FIGURE 2. A UCSD Strategy to Increase Nutrient Intakes of the Premature Infant After Discharge
If the MBM supply is anticipated to meet >75% of the infant’s daily feeding volume goal:
Provide 1 oz of 30 kcal/oz premature formula 3 to 4 times per day after breastfeeding, or with expressed breast milk when bottle feeding.
Guidelines include:
• Do not exceed 4 oz per day of the 30 kcal/oz premature formula
• Do not provide all 3 to 4 oz of 30 kcal/oz premature formula at one feeding
• Do not force the baby to finish all of the 30 kcal/oz formula. He/she may accept different amounts at different times of the day
UCSD = University of California—San Diego; MBM = maternal breast milk.
Example: A 2.2-kg infant receiving 160 mL/kg of this feeding strategy, which includes 3 oz/day of Gerber Good Start Premature infant formula (30 kcal/oz) = ~120 kcal/kg, 2.7 g protein/kg, 98 mg Ca/kg, and 50 mg Phos/kg.
TABLE 1. A UCSD Strategy to Increase Nutrient Delivery of Breast Milk for the Hospitalized Premature Infant
Breast Milk 20 Cal/oz 22 Cal/oz 24 Cal/oz 26 Cal/oz 28 Cal/oz*
Premature Infant
MBM or DBM†
(† When <1500 g or to bridge the gap until MBM is available)
50 mL MBM or DBM + 5 mL liquid human milk fortifier (HMF)
25 mL of MBM or DBM + 5 mL liquid HMF
25 mL of MBM or DBM + 5 mL of HMF + 5 mL of hydrolyzed 40 cal/oz liquid formula concentrate
25 mL* of MBM or DBM + 5 mL of HMF + 10 mL* of hydrolyzed 40 cal/oz liquid formula concentrate
UCSD = University of California—San Diego; MBM = maternal breast milk; DBM = donor breast milk.
*An alternate recipe option per registered dietician review due to higher potential renal solute load: 17 mL of MBM + 5 mL of liquid HMF (EHMF or SHMF) + 5 mL of Nutramigen® liquid concentrate = 28 cal/oz.
Dietitian acknowledges that some recipes include off-label use of products at the discretion of the medical team.Term liquid formula concentrates can be used to increase the caloric density of MBM for term infants. Example: 60 mL of MBM + 15 mL of 40 cal/oz infant formula liquid concentrate = 24 cal/oz MBM.Protein can be increased in MBM with the addition of Abbott Liquid Protein Fortifier: Add 3 mL of liquid protein to every 42 mL of MBM = 20 cal/oz MBM with ~3 g protein per 100 calories.
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Because postnatal growth is a major determinant of short- and long-term outcomes in extreme-
ly premature infants, the nutritional goal for these newborns is to reach a postnatal growth rate similar to that of the normal fetus of the same gestational age. Yet most of these infants gain less weight than do third-trimester fetuses, a deficit that results in extrauterine growth restriction (weight for gesta-tional age below the 10th percentile). And as Jackie Wessel, MEd, RDN—a neonatal nutritionist at Cincinnati Children’s Medical Center—pointed out, optimal growth in extremely pre-mature infants presents something of a dilemma: The goal is to improve growth so as to preserve neurodevelopment while minimizing too rapid a weight gain, which is associated with develop-ment of insulin resistance and metabolic syndrome later in life. It appears that the key is to diminish typical postnatal growth restriction in these infants; this will decrease the need for catch-up growth and reduce the risk of develop-ing cardiovascular risk factors.
Tools for monitoring growth. Achiev- ing growth goals is complicated by a lack of prescriptive growth charts. In 2013, Fenton and Kim revised the 2003 Fenton Preterm Growth Chart to conform with new World Health Organization growth standards, resulting in sex-specific actual-age growth charts based on recommended growth goals for preterm infants (see Figure 3).
The goal, Ms. Wessel said, is for the baby to have “continuing weight gain along the percentile or z score from birth.” For extremely premature infants whose weights are below the
third percentile, in the uncalibrated areas below the percentile curves on growth charts, calculating z scores—the standard deviation above or below
the mean—may be the best way to monitor growth since z scores more accurately describe growth for babies under the third percentile. The revised Fenton charts and related information, including how to procure z score cal-culators, can be found at http://www.ucalgary.ca/fenton/2013chart.
What the studies show. Research has shown how providing extremely pre-mature infants with nutrients soon
Finding better strategies for optimal weight gain in premature neonates
FIGURE 3. Fenton Preterm Growth Chart - Boys
Tanis FR, Jae KH. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatrics. 2013;13:59.
References Fenton R Tanis, Kim H Jae. A systemaEc review and meta-‐analysis to revise the Fenton growth chart for preterm infants. BMC Pediatrics.2013, 13:59
Growth chart valida.on study #1: Fenton TR, Nasser R, Eliasziw M, Kim JH et al.ValidaEng the weight gain of preterm infants between the reference growth curve of the fetus and the term infant. BMC Pediatr. 2013;13(1):92
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NUTRITIONAL INSIGHTS
after birth is positively associated with growth during the first month of life.4 Further, it appears that enhanced first-week protein and energy intakes are associated with increased mental development at 18 months, with high-er protein in the first week also tied to growth in length.5 Also notable, 1 study found that extremely premature infants can tolerate early aggressive intake of amino acids and fat emul-sions (eg, Intralipid), which signifi-cantly increases positive nitrogen balance and caloric intake without increasing the risk of adverse side effects.6 These and similar study affir-mations of early and cautiously aggres-sive nutrition are important, Ms. Wessel pointed out, because about 18% of extremely premature infants are below the 10th percentile for weight at birth, and even more—75%—fall below that percentile by discharge. When an NICU infant loses weight and drops a percentile, it is difficult to reclaim that loss, and the subnormal growth often persists into childhood.
Current nutritional strategies. “Many of our centers nowadays give protein right away, many in the first IVs,” Ms. Wessel observed. This is in the form of an amino acid–containing IV kept in the unit. Then total parental nutrition is written the next full day. It also must be kept in mind, Ms. Wessel stressed, that evaluation of neonatal nutritional adequacy in the premature infant is not determined by weight gain alone. Linear and proportional growth, as well as body composition (adequate lean body mass and limited fat mass), are also important. Tools for measuring body composition include the Olsen 2015 body mass index (BMI) curves for preterm infants, which report percen-tiles and z scores, and whole body den-sitometry, which measures fat and fat-free mass. A new technique relies on air displacement plethysmography, but this method has not yet been vali-dated in preterm infants.
Much remains to be learned about the cause of autism spectrum disorders (ASD),
but it appears to encompass a combi-nation of genetic, immunologic, and environmental elements, according to Alessio Fasano, MD, chief, division of pediatric gastroenterology and nutri-tion, Massachusetts General Hospital for Children. Many studies have established that certain gene mutations, especially on chromosomes 7 and 16, are linked to ASD, while other research has found associations with immune-system abnor-malities. Observers are paying increased attention to ASD environmental risk fac-tors—primarily nutrition—because the prevalence of this condition has explod-ed in too short a period to be accounted for by genetic mutations.
One theory is that we “did not evolve to deal with grains contain-ing gluten” (wheat, rye, and barley), instead evolving by eating fruits, nuts,
vegetables, and tubers, Dr. Fasano said. For this evolutionary reason, we don’t have the enzymes to completely digest gluten. This poses a particular problem for children with ASD because of their enhanced gut permeability (when these children are put on a gluten-free, casein-free diet, the permeability goes back to that of other children), so the undigested gluten stays in the gut for hours, stimulating the immune system to mount a response. The molecule zonulin controls the spaces between the cells of the intestinal lining, modulating gut permeability; when these spaces
FIGURE 4. Possible Gastrointestinal Dysfunctions in ASD
ASD = autism spectrum disorder; GI = gastrointestinal.
Adapted from Fasano A. Scientific American, Inc. 2009;60:38.
Dysbiosis causes zonulin release and
consequent leaky gut
ActivatedActivatedinflammatory cells cause local inflammation responsible for the GI symptoms experienced by a p ysubgroup of ASD children
Non-self antigens, including gluten, casein, and microorganisms bioproducts gain access
Activatedbioproducts gain accessinto the lamina propria
Antigen presenting cells (APC) present the non-self antigens to other immune cells
inflammatory cells migrate to the brain where they cause local inflammation responsible for behavioral symptoms typical of ASD
Diet and autism: Is there a connection?
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The market for gluten-free foods in this country is booming. In 2014, retail sales totaled almost
$2.6 million and are expected to reach $6.1 billion by 2017. Dr. Fasano reported that while it is generally known that someone with celiac dis-ease should follow a gluten-free diet, many who have adopted this regimen cite other reasons, for example a belief that gluten-free food is healthier, will help them lose weight, or will resolve their gastrointestinal (GI) and extra-GI symptoms. Though this suggests that a “fad factor” may well be part of gluten-free foods’ popularity, we now know that celiac disease is not the only health concern associated with gluten consumption—there actually are 3: • Celiac disease. In this heritable auto-immune condition, patients cannot tol-erate gluten because their body responds to it by mounting T cells in the GI mucosa, leading to damage of the villi and preventing the proper absorption of nutrients. Symptoms include those involving the GI system,
fatigue, weight loss, bone and joint pain, and migraine. • Wheat allergy. As with other food allergies, wheat allergy incites the immune system to release antibodies (eg, IgE), which causes other cells to release inflammatory substances such as histamine, resulting in a variety of symptoms, from mild skin reactions to anaphylaxis. Unlike celiac disease, however, wheat allergy does not cause severe intestinal damage.• Gluten sensitivity. In this condition, the body mounts a stress response—often GI symptoms—but neither autoimmune nor allergic mechanisms are involved. (Gluten sensitivity prob-ably is mediated by innate immunity, however.) Symptoms can be similar to those of celiac disease, with the most common being abdominal pain. Other symptoms include AD or rash; head-ache; “foggy mind”; fatigue; diarrhea; depression; anemia; numbness of the legs, arms, or fingers; and joint pain (see Table 2).8
The only way to diagnose gluten sen-
sitivity is to rule out both the allergic and autoimmune mechanisms that characterize wheat allergy and celiac disease, respectively. To illustrate how difficult it can be to diagnose gluten sensitivity, how debilitating its symp-toms can be, and the potential benefits of a gluten-free diet, Dr. Fasano pre-sented the case of a 19-year-old woman whose problems began with a 6-month history of recurrent abdominal pain and heartburn. Suspecting gastroesoph-ageal reflux disease (GERD), her physi-cian prescribed a proton pump inhibitor, which failed to relieve her symptoms. Not only did the patient’s
open up too much (what is called a leaky gut), larger protein molecules such as gliadin (a protein in wheat) get into the bloodstream and incite an immunologic reaction. And to com-plicate matters in children with ASD who already tend to have a leaky gut, it appears that gliadin activates zonulin production, leading to increased intestinal permeability (see Figure 4). (Interestingly, the genes that code zonulin are on chromosome 16—the very chromosome that “is packed with other genes that are related to autism,” Dr. Fasano noted.)
And what does this series of events have to do with ASD? One theory is
that because some of the undigested gluten peptides are structurally similar to the endorphins that control our behavior, these peptides traverse the blood-brain barrier, entering the brain and causing changes in behavior by interacting with endorphin receptors. Another possibility is that in autistic children, immune cells are pro-grammed to leave the gut and go to the brain, where they produce inflamma-tion associated with behavioral symp-toms typical of ASD. It also appears that an individual’s microbiome (the bacte-ria in the human body) is a determinant of the inflammatory effects of gluten.
Yet a meta-analysis of gluten- and
casein-free diets in ASD did not find that such regimens are a magic bullet for treating this condition.7 (Casein, found in dairy products, is another immune-activating and inflammatory protein.) Of 6 studies, 3 found that these diets were not effective, while the other 3 found only 3 significant treat-ment effects: overall autistic traits, social isolation, and overall ability to com-municate and interact. No differences could be analyzed for 10 outcomes because of poor data. The meta-analysis authors concluded that current evi-dence for the efficacy of this diet is poor and that large-scale, good quality, ran-domized controlled trials are needed.
Gluten-free diets: Separating the wheat from the chaff
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NUTRITIONAL INSIGHTS
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GERD symptoms persist, but she also developed headaches, dizziness, numb-ness in her fingers, paresthesia, and gradual reduction of muscle strength in her legs that became so severe she was confined to a wheelchair. After neuro-logic conditions, including multiple
sclerosis, were ruled out, the patient’s physicians also considered, and also ruled out, Lyme disease, Epstein-Barr virus, pernicious anemia, and lupus. The patient also was screened for celiac disease and tested negative. She none-theless decided to follow a gluten-free
diet, and within 3 weeks her GI symp-toms resolved. Further, within 2 months her neurologic symptoms also improved. Six months after beginning the diet she could walk with a cane, and 12 months later she had completely regained her ability to walk.
TABLE 2. Gluten Intolerance: More Than Celiac Disease
Celiac Disease (CD) Gluten Sensitivity (GS) Wheat Allergy (WA)
Time interval between gluten exposure and onset of symptoms
Weeks-Years Hours-Days Minutes-Hours
Pathogenesis Autoimmunity (innate + adaptive immunity)
Immunity? (Innate immunity?) Allergic immune response
Human leukocyte antigen (HLA)
HLA-DQ2/-DQ8–restricted (~97% positive cases)
Not HLA-DQ2/-DQ8–restricted (50% DQ2/DQ8 positive cases)
Not HLA-DQ2/DQ8–restricted (35%-40% positive cases, as in the general population)
Auto-antibodies Almost always present Always absent Always absent
Enteropathy Almost always present Always absent (slight increase in IEL)
Always absent (eosinophils in the lamina propria)
Symptoms Both intestinal and extra-intestinal (not distinguishable from GS and WA with GI symptoms)
Both intestinal and extra-intestinal (not distinguishable from CD and WA with GI symptoms)
Both intestinal and extra-intestinal (not distinguishable from CD and GS when presenting with GI symptoms)
Complications Comorbidities
Long-term complications
Absence of comorbidities and long-term complications (long follow-up studies needed to confirm it)
Absence of comorbidities
Short-term complications (including anaphylaxis)
GI = gastrointestinal; IEL = intraepithelial lymphocytes.
Debbie O’Connor, PhD, RD, professor, University of Toronto, Canada, focused on the efficacy
and safety of donor human milk com-pared with preterm formula as a sup-plement for premature infants. A mother’s own milk is, of course, the best food for all infants. As Dr. O’Connor noted, however, mothers may not be able to provide sufficient milk for a variety of reasons, perhaps because of illness, stress, or difficulty
pumping or because they have given birth at the beginning of their third trimester when the mammary secre-tory cells are quite immature and “it takes a while to get things going.”
But it’s important to realize that the donor milk available from milk banks differs from the milk a baby gets directly from his or her mother. Donor milk is frozen then thawed, and is pooled and pasteurized. At the donor milk bank with which Dr. O’Connor
is affiliated, milk is mixed from 3 dif-ferent mothers and, in addition to pas-teurization, undergoes 5 container changes and several freeze/thaw cycles, which affect both nutrients and bioactive components. For example, pasteurization destroys bile cell–dependent lipase (important for the digestion of fat), though the minerals
How good is donor milk for preterm babies?
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in human milk are not affected at all, and the cytokines that are important in the prevention of necrotizing enterocolitis (NEC)—a potentially fatal condition for which infants who weigh <1500 g are at risk—are only slightly affected.
A Cochrane meta-analysis of 9 trials involving more than 1000 preterm or low-birth-weight (LBW) infants tack-led the question of whether it is better to provide preterm formula with its optimal levels of nutrients or donor breast milk.9 Four trials compared stan-dard-term formula with donor breast milk, and 5 compared nutrient-enriched preterm formula with donor breast milk. In the most important finding, NEC was 2.77 times more likely to develop in babies fed formula than in those given donor milk. Donor milk also provided a slight advantage with regard to feeding tolerance (but only a few studies examined it). On the minus side, unlike with term and pre-term formula, donor milk was not associated with sufficient weight, length, and head circumference growth for optimal neurodevelopment. The authors noted, however, that because only 2 of the studies used the nutrient-fortified donor breast milk that is now so common, the applicabil-ity of their findings is limited. And a trial in 363 very LBW infants that did compare fortified donor breast milk with preterm formula found that forti-fication did not lessen the protective effects of donor milk as a supplement against NEC. Also, growth was similar in infants fed the fortified donor milk and those fed formula.10
As for donor milk for the term baby of normal weight, Dr. O’Connor said that the research in this area is “pretty thin.” Given that pasteurization and freezer storage reduces the nutrient content of donor milk, more work is required to ensure that donor milk as an exclusive form of nutrition can meet the needs of a healthy, term infant.
In introducing his talk on managing food allergies, Dr. Fleischer reviewed the categorization of food allergies
into 2 types: a) those mediated by IgE, which typically are characterized by hives, swelling, or another reaction (the most serious, anaphylaxis) often within 15 to 30 minutes after ingestion, and b) non-IgE mediated, where symptoms typically are delayed and rarely are life-threatening. Mixed immune-mediated disorders—IgE and non-IgE—also exist, as do cell-mediated food allergies. All these immune system–related disor-
ders are distinguished from food intol-erance (most often to lactose), which is not mediated by the immune system.
To address a suspected food allergy, the clinician needs to identify the foods to which the child is allergic by setting up an elimination diet with the fewest number of foods to be avoided. Once a specific food allergy is diagnosed, avoidance of that food can be implemented. Dr. Fleischer recom-mends that the family of a child with a food allergy meet with a nutritionist to review likely sources of accidental
TABLE 3. Food Allergy Patient/Provider Checklist
Did we:
– Verify that the family and/or child had auto-injectable epinephrine at the visit?
o Ask if the child is carrying auto-injectable epinephrine.
o Verify the auto-injectable device is intact.
o Double-check the expiration date on the auto-injectable device.
o Double-check the dose of the auto-injectable device and the patient’s weight.
– Demonstrate appropriate use of the auto-injectable epinephrine device?
– Ask the child’s caregiver to demonstrate appropriate use of the auto-injectable epinephrine device?
– Explain to the family their responsibility for always carrying auto-injectable epinephrine?
– Have the child demonstrate how to use an auto-injectable epinephrine device (if developmentally appropriate)?
– Ask the child to describe symptoms of anaphylaxis that would require the use of auto-injectable epinephrine?
o The previous 2 questions are more important if:
◾ The child has had more than 1 previous systemic allergic reaction.
◾ The child has experienced severe life-threatening anaphylaxis.
◾ Anaphylaxis is triggered by peanut or a tree nut.
◾ The child had a severe reaction from a very small amount of ingested allergen.
◾ The child has persistent asthma.
• If the child has asthma, specifically discuss the importance of control of asthma symptoms in order to reduce the likelihood of severe or fatal anaphylaxis.
– Review a food allergy action plan?
– Provide an updated food allergy action plan if it has been more than 1 year?
– Verify and/or recommend a medical ID bracelet?
– Provide avoidance handouts?
– Refill prescriptions?
Bird JA, et al. J Allergy Clin Immunol Pract. 2015;3:1-11.
Avoidance: The best (only!) way to manage food allergy
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The medical community has become increasingly aware of the importance of balanced
intestinal bacteria for healthy intesti-nal and immunologic development as well as for overall health. Kelly A. Tappenden, PhD, RD—a human nutrition, endowed professor at the University of Illinois—explored this subject by addressing what research has shown about how we can use probiotics (“good bugs”) and prebiotics (undigest-ible food elements that promote probi-otics’ growth) to prevent or ease health problems in children.
How intestinal bacteria affect infant development. “Contact with microbes begins in utero and proceeds in a stepwise manner during birth and early infancy,” Dr. Tappenden pointed out, noting the various functions of intestinal microbiota—especially to protect against pathogenic bacteria and aid in the development of immune and digestive/metabolic functions as well as neuronal development.12 Children’s microflora change in response to modifications in diet, antibiotics, and other events, which can result in an excess of harmful species or an absence
of beneficial species, leading to dys-functions such as intestinal inflamma-tion. This “dysbiosis” is also associated with certain conditions such as celiac disease, inflammatory bowel disease (IBD), atopy, irritable bowel syndrome (IBS), NEC, and cystic fibrosis.
Microbiota—breast milk vs formula. In breastfed infants, Bifidobacteria, one of the most beneficial of the intestinal bacteria, rapidly increase after birth, quickly predominating in these babies’ flora. Formula-fed infants, on the other hand, have far lower levels of Bifidobacteria and other beneficial bacte-ria. Because of this difference, probi-otic- and prebiotic-supplemented formulas are available to promote in formula-fed infants intestinal micro-biota similar to that of breastfed infants.
exposure, learn how to read labels (a far less challenging task than it used to be), and figure out what foods to substitute for any nutrients being eliminated. Families also need to develop a “food allergy action plan” that encompasses knowing what to do in case of acciden-tal exposure (treatment with epineph-rine, an antihistamine, or both), how to recognize early signs and symptoms of an allergic reaction, and having epi-nephrine available and knowing how and when to use it—namely, soon after exposure (see Table 3).11
In a follow-up visit after an allergic reaction, the clinician should: a) re- view the child’s response to treatment, the circumstances leading to the reac-tion, and the advisability of having the child wear a medical ID bracelet (or another form of food-allergic identifi-cation), and b) make any necessary changes to the action plan. Providing emotional support also is important. Long-term management consider-ations should include monitoring if the child has been exposed to the offend-ing food without having a reaction, making periodic reviews of his/her
diet, and determining whether the child has developed allergies to other foods or has developed another allergic disease, such as asthma. Depending on the findings, results of routine physical exams, impact of the allergy on quality of life, and any other relevant physical and psychological considerations, the clinician may want to consider skin or other testing or referral to an allergist, gastroenterologist, or psychosocial clinician.
Dr. Fleischer also tackled “peanut allergy misconceptions”—such as the belief that a child with peanut allergy is
at high risk of a reaction to public expo-sure of peanut by, for example, smelling peanut butter or being near peanut dust and that his environment must be “pea-nut-free.” In these and similar situa-tions, Dr. Fleischer said, “No protein is being released,” so the child is not at risk of an allergic reaction. Nonetheless, the preschool peanut-allergic child probably should eat at a peanut-free table, given that children of this age may pick up anything that looks appealing and put it in their mouths. “But once they turn 4 or 5 years old” and know what they can’t eat, Dr. Fleischer noted, “it’s more helpful to have those kids sit with their friends than be isolated at a table where they’re known as the food-allergic child.”
Though immunotherapy for allergy is available in 3 forms—oral, sublin-gual, and epicutaneous—this type of treatment has not been approved by the FDA. Further, Dr. Fleischer believes that immunotherapy currently should be used only in clinical trials because “we don’t have long-term data and really know which patients are going to respond best and to which therapy.”
How “good bugs” promote good health
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Support for probiotic and prebiotic use. Probiotics are living microorgan-isms found in foods and supplements as well as in the body. When consumed in sufficient quantities, probiotics exert health benefits, primarily by keeping the gut healthy. While specific probiot-ics have been found to have varying positive effects on preventing or easing a variety of conditions in children, the strongest evidence for their benefit is for diarrhea. Indeed, many trials have shown that probiotics can prevent the onset of antibiotic-associated diarrhea, with the 2 most effective strains being Lactobacillus rhamnosus GG (LGG) and Streptococcus boulardii. Also well estab-lished is the benefit of LGG and S bou-lardii in the treatment of acute watery diarrhea (primarily rotaviral), by reduc-ing its duration, and Lactobacillus in acute infectious diarrhea. Evidence also indicates that specific strains of probiot-ics can be useful in preventing or man-aging AD associated with cow’s milk allergy, IBS, and nonalcoholic fatty liver disease; decreasing crying time in infants with colic; and preventing NEC in premature infants (see Table 4).
Prebiotics are plant fibers that nour-ish good bacteria already in the intes-tines, promoting their growth. In a randomized trial in 134 formula-fed infants, those who received a prebiotic-supplemented formula were signifi-cantly less likely than those who received a placebo-supplemented for-mula to have symptoms of allergy—whether AD, recurrent wheezing, or allergic urticaria—during the first 2 years of life. The infants who received the prebiotic-supplemented formula also had fewer episodes of upper respi-ratory tract infections and fever and needed fewer antibiotic prescriptions.13 Studies have also found that the prebi-otic oligofructose reduces the likeli-hood of having a relapse of Clostridium difficile–associated diarrhea and that the prebiotic galactooligosaccharide allevi-ates symptoms of IBS.
Though the superiority of moth-er’s milk to any other infant feed is universally accepted, it now
seems clear that even this optimum food requires fortification when the infant is of a very LBW. Research in
105 preterm infants “that really got people talking,” according to Dr. O’Connor, showed that LBW infants rarely achieve nutrient intakes that meet current recommended dietary intakes, inevitably accumulating sig-
TABLE 4. When Probiotics May Help
Strong Evidence Supporting Probiotic Use
Clinical Condition Organism
Diarrhea
Infectious adult – treatment Saccharomyces (S) boulardii, LGG
Infectious child – treatment LGG, Lactobacillus (L) reuteri
Prevention of antibiotic-associated diarrhea
S boulardii, LGG, L casei, L bulgaricus, Streptococcus thermophilus
Inflammatory bowel disease
Pouchitis – preventing and maintaining remission
VSL#3a
Immune response LGG, L acidophilus, L plantarum, Bifidobacterium (B) lactis, L johnsonii, VSL#3a
Atopic dermatitis associated with cow’s milk allergy
Treatment LGG, B lactis
Moderate Evidence Supporting Probiotic Use
Diarrhea
Prevention of infection S boulardii, LGG
Treatment of recurrent C difficile–associated diarrhea
S boulardii, LGG
Prevention of recurrent C difficile–associated diarrhea
S boulardii, LGG
Necrotizing enterocolitis B infantis, Streptococcus thermophilus, B bifidum
Irritable bowel syndrome B infantis
LGG = Lactobacillus (L) rhamnosus GG.a The probiotic VSL#3 is a mixture of 8 different species of bacteria, namely Streptococcus salivarius subsp. thermophilus, L casei, L plantarum, L acidophilus, L delbrueckii subsp. bulgaricus, B longum, B infantis, and B breve.
When the neonate is preterm/tiny, mother’s milk needs fortification
NUTRITIONAL INSIGHTS
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nificant nutrient deficits in the first few weeks of life (see Figure 5). These deficits, which can be directly related to later growth retardation, will not be replaced when current recommended daily intakes alone are fed.14
A Cochrane review supported the view that fortified human milk can make up for such nutrient deficits by promoting growth in preterm infants. The meta-analysis found that multi-component fortifiers were associated with short-term increases in weight gain as well as in linear and head growth. Some of the included studies also saw an improvement in bone mineralization, but no long-term out-comes were measured.15 And a more recent study in more than 1000 infants born at 23 to 27 weeks’ gestation also found that early provision of nutrients is an important determinant of postna-tal growth.4
Dr. O’Connor briefly reviewed the types of milk fortifiers that are available. She talked about the old-fashioned but still widely used powders as well as the popular Prolacta, a liquid fortifier. Fortifiers can be bovine- (most common), soy-, or human milk–based, and many NICUs compound in the hospital pharmacy a mixture of liquid preterm formula with various commercial protein powders and minerals. NICUs vary greatly in their strategies for fortifying milk. But whatever the NICU’s policy, Dr. O’Connor recommends that, before discharge, the baby be put on the feeding regi-men planned for home to make sure the infant “is growing okay” before leaving the hospital.
REFERENCES 1. Du Toit G, Roberts G, Sayre PH, et al. Randomized trial
of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372:803-813.
2. Von Berg A, Filipiak-Pittroff B, Krämer U, et al. Allergies in high-risk schoolchildren after early intervention with cow’s milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) study. J Allergy Clin Immunol. 2013;131:1565-1573.
FIGURE 5. Nutrient Intake/Deficits in Preterm Infants in the First Week of Life
Embleton ND, et al. Pediatrics. 2001;107(2):270-273.
Energy (kcals/kg)
Cu
mu
lati
ve D
efici
tIn
take
150
100
50
0
-50
-100
-150
-200
-250
-300
-350
-400
-450
-500
-550
Postnatal Age (days)
1 2 3 4 5 6 7
≤30 weeks
≥31 weeks
P<.001*
*
*
Protein (g/kg)
Cu
mu
lati
ve D
efici
tIn
take
6
4
2
0
-2
-4
-6
-8
-10
-12
-14
-16
-18
Postnatal Age (days)
1 2 3 4 5 6 7
≤30 weeks
≥31 weeks
P<.001*
*
*
12
13
3. Koletzko B, Poindexter B, Uauy R. Recommended nutrient intake levels for stable, fully enterally fed very low birth weight infants. World Rev Nutr Diet. 2014;110:297-299.
4. Martin CR, Brown YE, Ehrenkranz RA, et al. Nutritional practices and growth velocity in the first month of life in extremely premature infants. Pediatrics. 2009;124:649-657.
5. Stephens BE, Walden RV, Gargus RA, et al. First-week protein and energy intakes are associated with 18-month developmental outcomes in extremely low birth weight infants. Pediatrics. 2009;123:1337-1343.
6. Ibrahim HM, Jeroudi MA, Baier RJ, et al. Aggressive early total parental nutrition in low-birth-weight infants. J Perinatol. 2004;24:482-486.
7. Millward C, Ferriter M, Calver S, et al. Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database Syst Rev. 2008;16(2):CD003498.
8. Catassi C, Bai JC, Bonaz B, et al. Non-celiac gluten sensitivity: the new frontier of gluten related disorders. Nutrients. 2013;5:3839-3853.
9. Quigley M, McGuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev. 2014;4:CD002971.
10. Unger S, Gibbins S, Zupancic J, O’Connor DL. DoMINO: Donor milk for improved neurodevelopmen-tal outcomes. BMC Pediatr. 2014;14:123.
11. Bird JA, Lack G, Perry TT. Clinical management of food allergy. J Allergy Clin Immunol Pract. 2015;3:1-11.
12. Buccigrossi V, Nicastro E, Guarino A. Functions of intestinal microflora in children. Curr Opin Gastroenterol. 2013;29:31-38.
13. Arslanoglu S, Moro GE, Schmitt J, et al. Early dietary intervention with a mixture of prebiotic oligosaccha-rides reduces the incidence of allergic manifestations and infections during the first two years of life. J Nutr. 2008;138:1091-1095.
14. Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics. 2001;107:270-273.
15. Kuschel CA, Harding JE. Multicomponent fortified human milk for promoting growth in preterm infants. Cochrane Database Syst Rev. 2004;(1):CD000343